6. Project Summary/Abstract Nephrogenic diabetes insipidus (NDI) due to lithium therapy for bipolar disorder is one of the major nephrological problems among Veterans. NDI is a debilitating condition with an elevated risk of morbidity and even mortality, especially in elderly Veterans. Currently used therapeutic modalities for NDI are encountered with varying degrees of success as well as side effects, including lithium intoxication. Refinement and/or replacement of the current side effect-prone therapies with new drugs based on an improved understanding of molecular pathophysiology of lithium-induced NDI should result in improved efficacy and fewer side effects. Research carried out by us during the current funding period provided significant insights into the potential role of purinergic signaling in the genesis of lithium-induced NDI. These are: (i) purinergic signaling may play a potential overarching role in balancing the effect of arginine vasopressin (AVP) on the urinary concentration mechanism; (ii) in lithium-induced NDI, purinergic signaling in the medullary collecting duct is sensitized and involves more than one subtype of P2Y receptors; and (iii) P2Y2 receptor gene knockout mice are significantly resistant to the development of lithium-induced NDI, suggesting the potential role of purinergic signaling in the genesis of lithium-induced NDI. Based on our novel and significant observations we hypothesize that a deeper understanding of the role of renal purinergic signaling in Li-induced NDI offers better therapeutic modalities. A new class of drugs that target purinergic signaling may improve the safety and/or efficacy of the current medications in combination therapies, or replace them in the treatment of Li-induced NDI. The specific objective of the project are: 1) to investigate the role of purinergic signaling in the development of Li-induced AVP resistance using P2Y2 receptor knockout and wild type mice; 2) to investigate the role of purinergic signaling in Li-induced AVP resistance of medullary collecting duct using primary cultures of mouse inner medullary collecting duct cells; and 3) to investigate the effect of amiloride and COX-2 inhibition on Li-induced NDI in a background of blunted purinergic signaling. To achieve our objectives we will use P2Y2 receptor knockout mice, rats and cell culture models, and employ molecular, functional, immunohistochemical and cell signaling techniques. PUBLIC HEALTH RELEVANCE: 7. Project Narrative Post-traumatic stress disorder, often seen in Veterans, predisposes them to bipolar disorder. Currently there are more than 27 million Veterans, of which about 4% suffer from bipolar disorders. About 30% of bipolar Veterans receive lithium treatment, which is the drug of choice because of low suicidal risk in lithium treated patients. However, the therapeutic use of lithium is associated with a major side effect, called nephrogenic diabetes insipidus (NDI). NDI is associated with morbidity and even mortality, if not treated properly. Currently used medications for the treatment of NDI have side effects and may not be safe all patients. The observations made by us on the potential role of purinergic signaling in lithium-induced NDI at this VA facility opened an avenue for the development of better therapeutic modalities for the treatment of lithium-induced NDI. This grant application proposes studies to further strengthen these concepts.